The National Cancer Institute has estimated that in the United States alone, 1 in 3 people will be struck with cancer during their lifetime. Moreover, approximately 50% to 60% of people contracting cancer will eventually succumb to the disease. The widespread occurrence of this disease underscores the need for improved anticancer regimens for the treatment of malignancy.
Immunostimulatory monoclonal antibodies (mAb) represent a new and exciting strategy in cancer immunotherapy to potentiate the immune responses of the host against the malignancy (Melero et al., Nat. Rev. Cancer, 7:95-106 (2007)). Such agonistic or antagonistic mAbs bind to key receptors in cells of the immune system acting to enhance antigen presentation (e.g., anti-CD40), to provide costimulation (e.g., anti-CD137), or to counteract immunoregulation (e.g., anti-CTLA-4).
Ipilimumab is a human anti-human CTLA-4 antibody which blocks the binding of CTLA-4 to CD80 and CD86 expressed on antigen presenting cells and thereby, blocking the negative downregulation of the immune responses elicited by the interaction of these molecules.
CD137 (also called 4-1BB) is a T-cell costimulatory receptor induced on TCR activation (Nam et al., Curr. Cancer Drug Targets, 5:357-363 (2005); Watts et al., Annu. Rev. Immunol., 23:23-68 (2005)). In addition to its expression on activated CD4+ and CD8+ T cells, CD137 is also expressed on CD4+CD25+ regulatory T cells, natural killer (NK) and NK-T cells, monocytes, neutrophils, and dendritic cells. Its natural ligand, CD137L, has been described on antigen-presenting cells including B cells, monocyte/macrophages, and dendritic cells (Watts et al., Annu. Rev. Immunol., 23:23-68 (2005)). On interaction with its ligand, CD137 leads to increased TCR-induced T-cell proliferation, cytokine production, functional maturation, and prolonged CD8+ T-cell survival (Nam et al., Curr. Cancer Drug Targets, 5:357-363 (2005), Watts et al., Annu. Rev. Immunol., 23:23-68 (2005)).
Many of the adverse events associated with ipilimumab treatment are a consequence of the intrinsic biological activity of ipilimumab, and its effects on T lymphocytes. The most common severe (≧grade 3) immune-related adverse events (irAE) are gastrointestinal-related (12%). In general, these adverse immune events have been associated with clinical response (Phan et al., Proc. Natl. Acad. Sci. USA, 100:8372-8377 (2003), Beck et al., J. Clin. Oncol., 24:2283-2289 (2006)), even in the absence of vaccination, suggesting that CTLA-4 blockade may be expanding autoreactive T cells. It has also been proposed that specific chemokine receptors expressed in the induced T cells may direct them to the intestine. Even though enterocolitis has been reported in melanoma subjects, administration of ipilimumab to healthy cynomolgus monkeys failed to detect this adverse event even after administration of multiple doses (unpublished results). Similarly, mice treated with multiple doses of CTLA-4 blocking antibodies did not develop clinical signs of colitis (Korman et al., Adv. Immunol., 90:297-339 (2006)).
In the studies reported herein, mouse colitis models for ulcerative colitis and Crohn's-like disease were used to investigate the effect of CTLA-4 blockade in animals prone to develop immune-mediated colitis. The ultimate goal of these studies was to determine how treatment with CD137 agonist mAb could modulate the course of immune-mediated colitis in animals treated with CTLA-4 blocking mAb.
Two models were used in these studies: a) Oxazolone-induced colitis, a mixed Th1/Th2 colitis model that has a histological and cytokine-pattern similar to human ulcerative colitis; and b) Trinitrobenzene sulfonic acid (TNBS)-induced colitis, a Th1-mediated model of chronic intestinal inflammation that resembles Crohn's disease. The mouse model for ulcerative colitis is based on the application of oxazolone, a haptenating agent, which after intrarectal challenge, induces colitis in the distal portion of the colon with histopathological and immunological features that resemble the human disease (Strober et al., Annu. Rev. Immunol., 20:495-549 (2002); Kojima et al., J. Pharmacol. Sci., 96:307-313 (2004)). The model of Crohn's disease is based on the intrarectal delivery of trinitrobenzene sulfonic acid (TNBS). The intestinal inflammation is driven by IL-12 and is mediated by activation of macrophages and CD4+ T cell infiltration in the lamina propria (LP).
The present inventors have discovered for the first time, a treatment regimen involving the combination of an agonistic CD137 antibody with an anti-CTLA-4 inhibitor that results in a significant benefit for the treatment of colitis. It is an object of the invention to provide efficacious combination treatment regimens wherein an agonistic CD137 antibody agent is combined with one or more anti-CTLA4 agents for the treatment of colitis diseases.